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PubMed1992

Combined effects of RU486 and tamoxifen on the growth and cell cycle phases of the MCF-7 cell line.

The antiproliferative effect of RU486 and its effect combined with tamoxifen on the growth and cell cycle kinetics parameters on the MCF-7 human carcinoma cells were investigated. When MCF-7 cells in the exponential growth phase were treated with RU486 (10(2) nmol/L), a time-dependent cell growth inhibition was observed which was significant 5 days after the beginning of treatment. This inhibition was accompanied by a time- and dose-dependent decrease in the percentage of S and G2-M phase cells and a concomitant increase in the percentage of cells in the G0/G1 phase of the cell cycle. With tamoxifen (10(5) pmol/L), growth inhibition was obtained after 4 days of treatment of cells, and the blockage of the cell cycle occurred in the G0/G1 phase. In the case of simultaneous treatment of MCF-7 cultures with RU486 (10(2) nmol/L) and tamoxifen (10(5) pmol/L), we observed a synergistic inhibitory effect on the proliferative rate for short treatment (less than or equal to 3 days), whereas RU486 or tamoxifen alone had no effect. For the intermediate treatment (4 days), the combined effect of RU486 and tamoxifen was not significant compared to the effect of tamoxifen alone. For the long treatment (greater than 4 days), there were no differences between the number of cells in the treated cultures under different experimental conditions, but all were inhibited compared to those in control cell cultures. This simultaneous treatment of cells does not induce any change in the distribution of cells in the different cell cycle phases compared to tamoxifen percentages. These results suggest that RU486 is a cell cycle phase-specific growth inhibitory agent, and a combination of antiestrogen/antiprogestin should be considered as a possible improvement in breast cancer endocrine therapy.

Breast Neoplasms↗
PubMed1976

Estrogen-receptor binding: relationship to estrogen-induced responses.

The relationship between nuclear binding of the receptor-estrogen complex (R-E) and estrogenic responses was examined. Nuclear-bound R-E was measured by the [3H] estradiol exchange assay, which permits the quantification of R-E as a function of either endogenous or non labeled estrogen. The quantity of nuclear R-E fluctuated as a function of blood levels of estrogen during the estrous cycle in the rat. This indicates that the accumulation of the R-E complex by the nucleus of uterine cells may be of physiologic significance and under the control of endogenous estrogen.

Animals↗
PubMed1976

Outcome of pregnancy after clomiphene therapy.

Of 159 pregnancies conceived after clomiphene therapy, 141 ended in childbirth, including seven sets of twins. There was a probable increase in the number of infants born with major malformations. These were exclusively to women who had not previously borne a normal infant. The incidence of malformed infants compares well with that published after gonadotropin therapy. The possibly higher incidence of malformations seen after drug-induced ovulation would therefore seem to be due to the underlying subfertility state and thus not a direct drug effect.

Abnormalities, Drug-Induced↗
PubMed1987

Plasma levels of levonorgestrel and free levonorgestrel index in women using NORPLANT implants or two covered rods (NORPLANT-2).

Plasma levels of levonorgestrel, sex hormone binding globulin (SHBG) and estradiol were studied during four years in 283 healthy women using either NORPLANT implants or two covered rods (NORPLANT-2). The women were randomized to use either type of implant. Both implant systems have previously been shown to have similar release rates of levonorgestrel. In both groups plasma levels of levonorgestrel decreased throughout the study, and there were no statistically significant differences between the two groups in mean plasma levels of levonorgestrel. During the study 8 women became pregnant. All pregnancies but one occurred after 35 months of implant use and only in women using the covered rods. No significant differences were seen between the women who became pregnant and the rest of the group using two covered rods with respect to plasma levels of levonorgestrel. SHBG capacity tended to be somewhat higher in women using the two covered rods. As levonorgestrel is to a great extent bound to SHBG, and in that form not biologically active, a "free levonorgestrel index" was calculated as a ratio between levonorgestrel and SHBG. This index was significantly lower in users of two covered rods than in users of NORPLANT implants at 1, 12 and 48 months of use. Women who became pregnant had significantly lower "free levonorgestrel index" than had the rest of the group. It is postulated that the difference in "free levonorgestrel index" between users of the two implant systems reflect differences in release rate, the covered rods having a lower release rate of levonorgestrel than NORPLANT throughout the observation period. It is concluded that "free levonorgestrel index" is a better parameter than levonorgestrel plasma levels to describe implant function, and to discriminate women who are at risk of pregnancy.

Adult↗
PubMed1978

Monitoring of ovulation induction.

The plasma hormonal patterns of the normal menstrual cycle have been reviewed. A consistent cyclic pattern of plasma hormone levels is observed in LH, FSH, estrogens, and progestins in the menstrual cycle. Other plasma hormones, such as ACTH, growth hormone, TSH, and PRL, as well as androgens and corticosteroids, fluctuate throughout the menstrual cycle without any consistent pattern during the ovulatory cycle. FSH, LH, E2, E1, P, T, and A levels during the induced ovulatory cycle are presneted for comparison. In the gonadotropin-induced ovulatory cycle most hormones behave in a manner similar to that in the normal ovulatory cycle, except for FSH levels, which rise continuously throughout the follicular phase of the cycle. Following ovulation in the gonadotropin-induced cycle, T rises above normal levels. Early in the clomiphene-induced ovulatory cycle, unlike the normal cycle, LH is distinctly elevated. Levels of both LH and FSH in the rest of the cycle simulate those in the normal cycle. However, T and A levels rise from the very beginning of clomiphene therapy and continue to rise throughout the clomiphene-induced ovulatory cycle. Levels of E and P are higher than in the normal ovulatory cycle, but a similar pattern is preserved. Because of the potential dangers of gonadotropin therapy, monitoring by frequent examination and laboratory tests is required. E monitoring is mandatory to evaluate follicular maturation, to time hCG administration, and to minimize hyperstimulation. Cervical mucus is an unreliable parameter for monitoring gonadotropin therapy alone. In addition to cervical mucus, plasma or urinary E should be monitored regularly. Clomiphene therapy is less dangerous than gonadotropin therapy. Because of its lesser risk, monitoring is rarely performed during clomiphene use. An active monitoring approach has been described. While this approach may not necessarily improve the outcome of clomiphene therapy, it may hasten the process of selecting the appropriate dose. Although other ovulation-inducing agents are available, their use is rarely associated with serious medical complications, and monitoring would seem unnecessary.

Cervix Mucus↗
PubMed1986

Pituitary function and DHEA-S in male acne and DHEA-S, prolactin and cortisol before and after oral contraceptive treatment in female acne.

Pituitary function (TRH-LHRH stimulation test) was investigated in male acne patients and serum levels of dehydroepiandrosterone sulphate (DHEA-S), sex hormone binding globulin (SHBG) and other biochemical parameters were investigated in male acne patients and in female acne patients before and after treatment with an oral contraceptive. The TRH-LHRH stimulation test was performed with 15 male patients suffering from severe cystic acne and 7 healthy volunteers. Basal and stimulated prolactin, LH and FSH levels were statistically similar in the patients and control groups. However, the stimulated LH levels of the patients were 60% higher than those in controls. SHBG levels were significantly) higher in the patient group compared to those in the control group. Thirty-three female acne patients were randomly divided into two groups and treated for six months with an oral contraceptive containing 0.030 mg ethinylestradiol (EE) plus 0.150 mg levonorgestrel or 0.150 mg levonorgestrel. After six months' treatment a 30% decrease in DHEA-S levels were observed in the desogestrel/EE group and a 15% decrease in the levonorgestrel/EE group; the difference was not statistically significant. At the same time serum total cortisol increased by 75-100% and free testosterone fell by 30-40% in both groups, whereas SHBG elevated 250% in the desogestrel/EE group and 30% in the levonorgestrel/EE group. Acne improved significantly in both groups, desogestrel/EE showing greater improvement. A decrease in SHBG and increase in DHEA-S levels appear to be the most common hormonal changes in acne. Oral contraceptive treatment induces an increase in SHBG and decrease in DHEA-S and also improves acne.

Acne Vulgaris↗
PubMed1977

Pharmacologic modification of the time course of ovum transport in guinea pigs.

Various agents were examined for their effects on ovum transport in the guinea pig. Estrogen significantly accelerated ovum transport in this species. The experiments further demonstrated that estrogen did not act by inducing prostaglandin synthesis, nor by altering plasma progesterone levels. The estrogen-induced acceleration was significantly antagonized by tamoxifen, an antiestrogen that acts by interfering with estrogen receptor synthesis. Cycloheximide also antagonized the effects of estrogen on ovum transport. These data suggest that the modification of ovum transport by estrogen is due to the entrance of estrogen into the nuclei of target cells, and subsequent protein synthesis. Although we assume that this action occurs at the level of the oviduct, our experiments do not prove this assumption.

Animals↗
PubMed1976

[Gonadal function of rats following pre- or postnatal administration of some hormones (author's transl)].

Some steroid hormones as well as clomiphene have been administered to new-born rats (postnatally) or to pregnant rats (prenatally) in order to study the effect on the future gonadal function of the animals born before or after the injection. A single postnatal androgen injection in oily solution influences only the female function; estrogen or the combination of androgen and estrogen are effective in both sexes preventing the ovulation or damaging the testicles. If the hormone is administered in water instead of oil, several injections are necessary in order to obtain an effect. Only the aqueous solution of clomiphene produces a positive effect even given in a single injection. When a single postnatal injection is effective the same result can be obtained after prenatal administration but only following intraamniotic injection. Clomiphene is an exception to this rule; intraamniotic injection has no effect. These observations permit the following conclusions: 1. It is possible to influence the hypothalamus-hypophysis function not only in the first days of life but already in the prenatal period. 2. As androgen damages only the ovary, estrogen however the gonads of both sexes, the mechanisme of action can not be the same. Androgen alters the function of the sexual centres in the brain only in the female rat, estrogen paralyses this function in both sexes. 3. Prenatal injection of hormone is only effective if administered intraamniotically (eliminating in this way the action of the placenta). This proves the important role of the placenta in the metabolisme of the hormones. 4. Other possible consequences of postnatal androgen administration as permanent obstruction of the vagina or hypertrophy of the clitoris can be obtained equally by prenatal intraamniotic injection. These phenomena can also occur independent of the avarian processes, being due to direct hormonal action. 5. Tubo-ovarian inflammation and abscesses are observed with relative frequency especially following estrogen or clomiphene-administration. The cause is unknown but we can assume that circulatory disorders in the genital area, produced by the hormone, are responsible for the frequency of these phenomena.

Androgens↗
PubMed1985

Ultrasonic visualization of NORPLANT subdermal contraceptive devices.

This article describes the first use of ultrasound in locating in vivo NORPLANT subdermal contraceptive implants. Providing low dose, continuous contraception for women. the NORPLANT system utilizes Silastic tubing filled with levonorgestrel. The progestin-filled tubing is not radiopaque. Anticipating the large scale use of NORPLANT subdermal implants, the potential, but rare problem of difficult localization of an implant is recognized. The feasibility of using ultrasound for the painless and safe localization of NORPLANT rods and capsules is demonstrated.

Arm↗